Download copper toxicity in dogs

COPPER TOXICITY
IN
DOGS
Robert H. Presley, DVM
Resident, Small Animal Internal Medicine
Douglass K. Macintire, DVM, MS, DACVIM, DACVECC
Professor
Department of Clinical Sciences
Auburn University College of Veterinary Medicine
A
cute copper toxicity is exceedingly rare in small
animals. In the few reported cases, copper toxicity has been associated with the ingestion of
copper-containing solutions such as fungicides, algicides, and large-animal footbaths. Most coins produced in the United States contain a significant
amount of copper, but toxicity from ingestion is
exceedingly rare. Pennies manufactured after 1982
contain higher levels of zinc, which is the source of
toxicity if ingested.
Chronic copper toxicity is more common than acute
toxicity in small animals and is usually the result of
defective copper excretion pathways or copper accumulation secondary to chronic hepatitis. Although
many breeds are suspected of having primary copper
accumulation because of defective biliary excretion,
only Bedlington terriers have been proven by DNA
analysis to be affected by this disorder. The underlying
cause of decreased copper excretion in other breeds is
thought to be a secondary phenomenon related to
cholestasis. Normal dogs generally have less than 400
ppm (µg copper/g per dry weight liver). However, as
the copper levels increase, the binding capacity of metallothionein becomes exceeded, allowing for release of
free copper into the hepatic cytosol. It is suspected that
the free copper then damages the mitochondria, initiating reactive oxygen species formation and lipid peroxidation and leading to hepatocyte death. Morphologic
evidence of direct hepatic injury occurs as concentrations of copper exceed 2,000 ppm, although submorphologic changes may occur at much lower levels.
Concentrations greater than 2,000 ppm are most likely
direct causes of hepatic injury, and levels below 1,000
ppm are most likely secondary to chronic hepatitis and
cholestasis.
Age Predisposition
• Acute toxicity: None.
• Chronic toxicity:
— Bedlington terriers and cocker spaniels appear
to be affected at very young ages (younger than
2 years of age).
DIAGNOSTIC CRITERIA
Physical Examination Findings
Historical Information
• Acute toxicity: Dehydration, stomatitis or oral
ulceration, icterus.
• Chronic toxicity: Varies with the stage of disease;
however, clinical signs may develop acutely, even
in chronic disease.
— Lethargy.
Gender Predisposition
• Acute toxicity: None.
• Chronic toxicity: Female Doberman pinschers
appear to be more commonly affected with chronic
active hepatitis than males. No predisposition
occurs in other breeds.
STANDARDS
of CARE: e M e r G e N C y
— Other predisposed breeds typically develop
clinical signs between 3 and 7 years of age.
Breed Predisposition
• Acute toxicity: None.
• Chronic toxicity: Bedlington terriers, West Highland
white terriers, Doberman pinschers, cocker spaniels,
Labrador retrievers, Dalmatians, Skye terriers.
Owner Observations
• Acute toxicity: Owners may witness ingestion of
copper-containing compounds or treated water.
However, owners most commonly report an acute
onset of gastrointestinal (GI) upset, including anorexia, vomiting, diarrhea, or corrosive oral injury.
• Chronic toxicity: Patients typically exhibit more
nonspecific signs attributable to liver failure, such
as lethargy, weight loss, polyuria or polydipsia,
icterus, or abdominal distention.
Other Historical Considerations/Predispositions
• Acute toxicity is more likely to occur in areas near
private ponds, golf courses, or ornamental fountains
where fungicides or algicides are added to water to
prevent contamination.
• Affected animals may have access to barns housing
large animals because copper compounds are commonly used to treat hoof injury.
— Cachexia.
5
AND
CrITICAL
CAre
MeDICINe
ON
THE
NEWS
• Coagulation panel: elevations in prothrombin time
(PT) and partial thromboplastin time (PTT) have been
reported secondary to hepatoxicity but are rare. $
• Complete blood count: Anemia secondary to acute
hemolysis may occur but is also rare. $
FRONT
— Although many breeds are suspected of
having primary copper excretion defects, it
has only been proven by DNA analysis in
Bedlington terriers.
— An autosomal recessive defect in the
MURR1 gene on chromosome 10, which
prevents proper excretion of copper into
bile, has recently been found.
Chronic Toxicity
• Serum chemistry profile: $
— Liver enzyme activity: ALT and AST elevations
most commonly occur secondary to hepatocellular damage. These values often exceed five to
18 times normal reference ranges (ALT, 26–200
U/L; AST, 15–50 U/L). ALP activity may also be
increased because of cholestasis, but it generally does not exceed the activity of ALT or AST
as seen with steroid hepatopathies. However,
in end-stage disease, these values may return to
or fall below normal reference ranges.
— Bile acids and total bilirubin: elevations may
occur secondary to liver dysfunction and
cholestasis or, rarely, because of intravascular
hemolysis.
— Hypoalbuminemia and hypocholesterolemia
may be present because of hepatic insufficiency.
— Decreased blood urea nitrogen and hyperammonemia may be present because of decreased
hepatic conversion of ammonia to urea.
— Hypoglycemia may be present with hepatic
insufficiency or secondary sepsis.
• Coagulation panel: $
— Prolonged PT and PTT may be noted secondary
to decreased hepatic production of coagulation
factors.
— Thrombocytopenia may occur secondary to
disseminated intravascular coagulation (DIC).
• Complete blood count: $
— Anemia: Most often the patient has mild, normocytic, normochromic nonregenerative anemia secondary to chronic disease. On rare
occasions, more severe anemia may occur secondary to acute hemolysis.
— Leukocytosis: If present, it is generally a mild,
mature neutrophilia.
— Thrombocytopenia: The degree of thrombocytopenia varies. Most commonly, the value is
within reference range unless secondary DIC
develops.
• Urinalysis: $
— Isosthenuria often occurs secondary to polyuria
and polydipsia and decreased hepatic urea production.
— Bilirubinuria may be present if total bilirubin
exceeds renal threshold.
— Veterinary Genetic Services (VetGen.com)
has developed a genetic linking test for
Bedlington terriers. Using a soft cheek
brush, DNA is analyzed for two alleles
(1 and 2) to detect diseased animals. Allele
1 is linked with a normal gene, and allele
2 is linked with disease. If a dog is 1/1,
then it is 90% likely that the animal is
homozygous normal. Dogs with 2/2 alleles
have a 72% chance of being affected, and
24% of them are carriers. Dogs with 1/2
alleles are also considered to be carriers.
This test can easily be completed by 6 to
10 weeks of age in puppies before they are
placed in homes.
— even with the success of this testing, liver
biopsy is still the current gold standard. To
determine the disease status of a Bedlington
terrier, a liver biopsy should be performed at
6 months and repeated at 15 months of age.
Most heterozygous animals have increased
copper levels at 6 months and then return
to normal by 15 months of age. Homozygous affected animals continue to have
increased levels at the second biopsy and
should receive preventive therapy.
— Icterus.
— Ascites.
— Fever.
— Petechiae or ecchymoses.
— Seizures.
Laboratory Findings
Acute Toxicity
In most cases, abnormalities are mild and consistent
with dehydration caused by GI disease.
• Serum chemistry profile: elevations in alanine aminotransferase (ALT), alkaline phosphatase (ALP), and
aspartate aminotransferase (AST) may occur if severe
toxicity is caused by hepatotoxicity. Bile acids and
total bilirubin may also be increased secondary to
liver dysfunction, cholestasis, and, rarely, hemolysis. $
6
J A N U A R Y / F E B R U A R Y
2 0 0 8
V
O
L
U
M
e
1
0
.
1
— Hemoglobinuria is extremely rare but is possible if intravascular hemolysis occurs.
• Serum copper and ceruloplasmin concentrations:
Unlike with Wilson’s disease (an inherited and
potentially fatal copper storage disease in humans),
these values are normal in dogs with chronic copper
toxicity. $
RESOURCE LIST
• Colorado State University’s diagnostic laboratory
uses atomic absorption spectroscopy to definitively quantitate hepatic copper content. The
service is offered for both needle and surgical
biopsy samples. The laboratory can be reached
by phone at 970-297-1281.
Other Diagnostic Findings
• Abdominal radiography is often unremarkable
unless microhepatia is present with chronic toxicity
or primary hepatitis. Generalized loss of serosal
detail may occur if ascites is present. $
• Abdominal ultrasonography: With chronic disease,
the liver often has generalized hyperechogenicity
because of fibrotic change. Less commonly, hyperor hypoechoic nodules may be present and may
represent functional “islands” of hepatic tissue or
areas of extramedullary hematopoiesis. If fibrosis is
severe, multiple acquired portosystemic shunts or
ascites may be evident. $
• Histopathology: $$–$$$
— On routine hematoxylin and eosin stains, hepatitis is characterized by lymphocytic–plasmacytic inflammation with piecemeal necrosis
(necrosis of hepatocytes adjacent to the periportal tract) and occasional bridging necrosis.
Variable amounts of fibrosis and cirrhosis occur
depending on the stage of disease.
— Histochemical stains such as rhodanine and
rubeanic acid can be used for semiquantitative
evaluation of copper accumulation in the liver.
Copper-containing lysosomes can typically be
detected when values exceed 400 ppm. In animals with a primary copper excretion defect,
these lysosomes tend to accumulate in a centrilobular pattern. In contrast, copper accumulation secondary to chronic hepatitis tends to
have a periportal distribution consistent with
cholestasis. Hepatic copper content can be
definitively quantitated by atomic absorption
spectroscopy.
Summary of Diagnostic Criteria
• Acute toxicity: Diagnosis may be confirmed with
owner observation of ingestion. The presence of
stomatitis and oral ulceration with acute GI disease
should raise suspicion of acute toxicity.
• Chronic toxicity:
— Histopathology or hepatic copper quantification is the gold standard for diagnosis at this
time. However, DNA analysis for specific
breeds is now being developed, which may
allow treatment to be initiated before development of hepatitis.
STANDARDS
of CARE: e M e r G e N C y
— Mild elevation of ALT or AST in predisposed
breeds warrants a thorough diagnostic workup
to minimize long-term effects.
Diagnostic Differentials
Acute Toxicity
• Zinc toxicity: With ingestion of pennies (or other
coins), clinicians may often attribute clinical signs,
such as acute hemolysis, to copper toxicity when
zinc toxicity is the true cause. Hemolysis secondary
to copper toxicity is extremely rare.
• Acute gastroenteritis is most commonly seen in
patients with acute toxicity. Other causes of GI upset
(e.g., foreign body, parvovirus infection in young
animals, dietary indiscretion) should be evaluated.
• Vitamin K antagonism: Although rare, bleeding
diathesis may occur, resulting in prolongation of
clotting times (PT and PTT) with acute copper toxicity. However, if this develops, it is associated with
fulminant liver failure, which should be apparent on
the serum chemistry profile. Generally, liver
enzyme activity remains normal with vitamin K
antagonism.
Chronic Toxicity
• Chronic active hepatitis: Copper accumulation
may occur in many breeds because of chronic
active hepatitis. Copper quantification of liver biopsies is crucial in determining whether copper excess
is the inciting cause of disease or secondary to
cholestasis. Generally, copper levels above 2,000
ppm are consistent with primary disease, and levels
below 1,000 ppm indicate secondary disease.
• Portosystemic shunt: Laboratory values and clinical
signs in animals with portosystemic shunt may be
similar to those seen in chronic copper toxicity.
However, the patient’s age and breed can be instrumental in designing a diagnostic protocol. Typically, only Bedlington terriers and possibly cocker
spaniels develop laboratory or clinical abnormalities before 2 years of age. However, many patients
with end-stage hepatitis may develop multiple
shunts if fibrosis becomes severe.
• Hepatotoxins: Other hepatotoxins (e.g., sago palm,
drug toxicity) may cause a similar presentation.
7
AND
CrITICAL
CAre
MeDICINe
Often these toxins can be easily differentiated by
previous exposure or administration of medications.
• Neoplasia: Hepatic or biliary neoplasia should be
ruled out using techniques such as abdominal radiography or ultrasonography, especially in older animals with apparent liver disease.
— Zinc gluconate: 1 mg/kg PO q8h 30 minutes
before feeding. $
• Vitamin E: 100–400 IU PO q24h as an antioxidant. $
Alternative/Optional
Treatments/Therapy
Acute Toxicity
• None.
TREATMENT
RECOMMENDATIONS
Chronic Toxicity
• S-Adenosylmethionine is a precursor of glutathione,
which provides antioxidant effects in the liver.
Dosage: 20 mg/kg PO q24h. $
• Ursodeoxycholic acid is believed to contain some
immunomodulating properties to decrease hepatic
damage, most likely by displacing hydrophobic bile
acids. Dosage: 15 mg/kg PO q24h. $
• Prednisone may be beneficial for patients with copper toxicity secondary to chronic active hepatitis by
reducing inflammation. However, if copper accumulation is primary (e.g., in Bedlington terriers and
possibly other breeds), prednisone should not be
used. Also, if significant fibrosis is present, prednisone may be of little to no benefit. Dosage: 2.2
mg/kg PO q24h and then tapered as liver enzyme
activity improves. $
Initial Treatment
Acute Toxicity
• Oral administration of milk or activated charcoal
should be performed to minimize epithelial damage
if the animal is not vomiting.
• Chelating agents: $
— D-penicillamine: 10–15 mg/kg PO q12h on an
empty stomach.
— Trientine: 10–15 mg/kg PO q12h on an empty
stomach.
Chronic Toxicity
• Dietary restriction: Most commercial diets contain
copper levels that are in excess for dogs with primary
copper excretion defects. Commercial diets such as
royal Canin Veterinary Diet Canine Hepatic LS 14
are restricted in copper and contain many antioxidants that help control oxidative damage. Home
diets may also be formulated, but ingredients such as
shellfish, mushrooms, organ meats, nuts, legumes,
and cereals high in copper should be avoided. Protein restriction should also be implemented if the
patient has signs of hepatic encephalopathy. $
• Chelating agents are most commonly used to
reduce hepatic copper levels.
— D-penicillamine: 10–15 mg/kg PO q12h on an
empty stomach. $
— Trientine: 10–15 mg/kg PO q12h on an empty
stomach. $
• Zinc therapy may be used as a primary therapy but
is most commonly used for maintenance therapy
after primary decoppering with D-penicillamine or
trientine has been performed. To prevent copper
deficiency, it is recommended that zinc therapy not
be combined with these drugs. Zinc decreases
intestinal copper absorption by inducing synthesis
of enterocyte metallothionein. Copper binds more
avidly than zinc, causing increased fecal loss with
normal enterocyte exfoliation. To prevent toxicity,
plasma zinc levels should be measured every 2 to 3
months and maintained at 200 to 500 μg/dL.
— Zinc acetate: 50 mg PO q12h 30 minutes
before feeding (maintenance dose). Some
authors recommend 100 mg PO q12h for 3
months if other chelators are not used. $
8
J A N U A R Y / F E B R U A R Y
2 0 0 8
V
O
Supportive Treatment
• Fluid therapy should be initiated if the patient is
dehydrated or in shock. Care must be taken with
aggressive crystalloid therapy because many
patients with liver disease have hypoalbuminemia,
which may potentiate ascites or edema. Colloidal
support may be beneficial in these circumstances. $
• Blood products: Fresh whole blood or fresh-frozen
plasma may be required for patients with coagulation perturbances. Whole blood or packed red
blood cells may be beneficial in rare occurrences of
hemolysis. Caution should be used in patients with
clinical signs consistent with hepatic encephalopathy because stored blood products may contain
high levels of ammonia. $
• Antiemetics may be beneficial in animals that are
vomiting. $
• Gastroprotectants: H2 blockers, proton pump
blockers, or sucralfate may be beneficial in animals
with acute copper toxicity; many patients with
hepatic failure are predisposed to GI ulceration. $
• Antibiotics are generally recommended in patients
with acute toxicity because bacterial translocation
may occur secondary to caustic GI ulceration. $
Patient Monitoring
• Most patients with acute copper toxicity only
exhibit GI signs and recover with supportive therL
U
M
e
1
0
.
1
apy. However, liver enzymes and hematocrit
should be monitored closely to ensure that hepatotoxicity or hemolysis does not occur. These complications are uncommon but may occur if excessive
copper levels are absorbed.
• Liver enzyme activity should be measured at least
two to four times a year in animals with chronic
copper toxicity and in predisposed breeds. If zinc
therapy has been instituted, plasma levels should be
measured every 2 to 3 months.
Home Management
• Owners of predisposed breeds should be educated
on the severity of chronic copper toxicity, and preventive measures should be initiated early in the
animal’s life.
• Dogs should not be allowed access to ponds, lakes,
or fountains treated with copper-containing fungicides or algicides.
• Copper chelators and zinc must be given on an
empty stomach. Giving these medications with
food substantially decreases their efficacy.
Milestones/Recovery Time Frames
• Acute toxicity: Most animals with acute copper toxicity recover within 3 to 5 days as the corrosive
lesions in the GI tract resolve.
• Chronic toxicity, whether primary or secondary to
chronic hepatitis, is typically a lifelong disease.
Unfortunately, most animals that are presented with
clinical signs of hepatic failure may succumb to disease within days to a few months because of the
severity of hepatic fibrosis. However, with early
diagnosis and treatment, many of these patients survive for months to years. For example, if copper
accumulation is detected at an early age, many
Bedlington terriers may live a normal lifespan if
treatment is initiated early.
STANDARDS
of CARE: e M e r G e N C y
Treatment Contraindications
• Emesis is not recommended if clinical signs are present because of the caustic nature of copper salts.
• Vitamin C: Although vitamin C has antioxidant properties, it has been shown to promote further lipid peroxidation in the presence of copper. $
PROGNOSIS
Favorable Criteria
• Acute toxicity: Clinical signs only attributable to GI
ulceration.
• Chronic toxicity:
— Diagnosis before liver enzyme elevation
(Bedlington terriers).
— Decrease in liver enzyme activity with therapy.
Unfavorable Criteria
Acute toxicity: Liver enzyme elevation, acute hemolysis.
Chronic toxicity: Severe liver fibrosis or cirrhosis, ascites,
coagulation abnormalities, hepatic encephalopathy.
RECOMMENDED READING
Hoffmann G, van den Ingh TS, Bode P, rothuizen J: Copper-associated chronic hepatitis in Labrador retrievers. J Vet Intern Med
20:856–861, 2006.
Oswiler GD: Toxicology. Philadelphia, Lippincott Williams and
Wilkins, 1996, pp 185–187.
Twedt DC: Copper-associated liver disease in the dog. Proc
ACVIM:412–416, 2006.
Ubbink GJ, Van den Ingh TS, yuzbasiyan-Gurkan V, et al: Population dynamics of inherited copper toxicosis in Dutch Bedlington terriers (1977–1997). J Vet Intern Med 14:172–176, 2000.
Webb CB, Twedt DC, Meyer DJ: Copper-associated liver disease
in Dalmations: A review of 10 dogs (1998–2001). J Vet Intern
Med 16:665–668, 2002.
Willard MD: Inflammatory canine hepatic disease, in ettinger SJ,
Feldman eC (eds): Textbook of Veterinary Internal Medicine.
Philadelphia, WB Saunders, 2004, pp 1442–1447.
9
AND
CrITICAL
CAre
MeDICINe